Autoimmune diseases are considered to be induced by autoreactivity acquired by lymphocytes that originally does not respond to themselves, or by incomplete removal of autoreactivated lymphocytes in the thymus and the like. In particular, rheumatoid arthritis (RA) is considered to be induced by immune response of lymphocytes, particularly T cells and B cells, against type II collagen that mostly exists in one's own joints. The disease gets serious because it accompanies infiltration of T cells and B cells into the joints, activation and proliferation of these cells in the joints and, when it advances, abnormal proliferation of synoviocytes in the joints to result in articular destruction. Because a number of activated lymphocytes infiltrate into articular tissues of RA patients, activated lymphocytes are considered to play an important role in the formation and advance of the disease state of RA.
In general terms, it is known that when lymphocytes are activated by antigen, type 1 helper T cells (Th1 cell) in the lymphocytes produces cytokines such as interleukin 2 (IL-2), interferon γ (IFN-γ) and the like, and the produced IL-2 and IFN-γ cause growth and division of lymphocytes, particularly T cells. Despite the presence of a great number of activated lymphocytes in the articular tissues of RA patients, IL-2 level is extremely low, which has produced a presumption that a lymphocyte growth factor should be present besides IL-2 (Journal of Experimental Medicine, vol. 168, p. 1573, 1988).
Recently, interleukin 15 (IL-15) was cloned as a new cytokine that promotes growth and differentiation of lymphocytes (T cells or B cells) (Science, vol. 264, p 965, 1994). The IL-15 receptor has been clarified to consist of α chain specific to IL-15, β chain common to IL-15 and IL-2, and γ chain common to the receptors of IL-15, IL-2, IL-4, IL-7, IL-9 and IL-13 (EMBO Journal, vol. 13, p. 2822, 1994; EMBO Journal, vol. 14, p. 3654, 1995). The presence of a signal transduction pathway via tyrosin kinase (represented by JAK1 and JAK3) in the downstream of β chain and γ chain has been also uncovered (Science, vol. 266, p. 1782, 1994). It is expected, therefore, that the pharmacological activity induced by the binding of IL-15 and IL-15 receptor is the promotion of proliferation of lymphocytes, and is almost of the same nature as the binding of IL-2 and IL-2 receptor. It has been reported that the IL-2, IL-9-producing cells are T cells, particularly helper T cells activated by antigen, the IL-7-producing cells are mostly stroma cells, and IL-15-producing cells are macrophages, dendritic cells, synoviocytes and the like (Science, vol. 264, p. 965, 1994). A recent report has documented that synovial fluid of RA patients has a markedly high concentration of IL-15, which suggests the important role of IL-15 as a growth factor for the proliferation of activated lymphocytes in the joints in RA. In addition, there is a report on many activities of IL-15 besides promotion of proliferation of the activated lymphocytes, such as promotion of migration of T cells toward inflammatory sites, activation of memory T cells, promotion of production of inflammatory cytokines such as tumor necrosis factor (TNF)-αand the like, and other activities (Nature medicine, vol. 3, p. 189, 1997). It is being elucidated that IL-15 plays an important role in the onset and development of various autoimmune diseases such as Crohn's diseases, lupus-nephritis in systemic lupus erythematosus and the like.
From the foregoing, it is considered that, for the improvement of symptoms of autoimmune diseases represented by RA, inhibition of proliferation of IL-15-dependent activated lymphocytes is particularly effective.
Conventionally, a therapeutic agent for autoimmune diseases, particularly RA, has been a gold compound, penicillamine, bucillamine, azathioprine, cyclophosphamide, methotrexate and the like. These inhibit proliferation of synoviocytes in the joints. Due to their antagonistic inhibitory action in nucleic acid metabolism, however, the long-term use of the agent is associated with highly frequent occurrence of side effects, such as hematopoietic injury, digestive system disorder and the like. Combined with easy infectivity and the like caused by the agents, they are not therapeutically satisfactory. While corticosteroid is effective for these diseases, it is associated with serious side effects, such as moon face, hypoadrenalism, osteonecrosis of femoral head and the like. Furthermore, leflunomide approved as an antirheumatic drug in the US has been reported to show a long half-life of blood disappearance despite its superior therapeutic effect, causing side effects such as digestive system disorder, liver disorder, eruption and the like (The Lancet, vol. 353, pp. 259–266, 1999), and a clinically more superior therapeutic agent is desired.
Thus, there is a strong demand for a therapeutic agent for autoimmune diseases such as RA and the like, which shows a superior therapeutic effect as compared to conventional pharmaceutical agents and which causes less side effects.
As mentioned above, the proliferation of activated lymphocytes in articular tissue is deeply involved in the progress of arthritis in RA, and IL-15 is suggested to be responsible for the proliferation of activated lymphocytes. Therefore, a compound that inhibits signal transduction via tyrosine kinase originated from IL-15 receptor (γ chain common to IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15) is considered to show a superior effect for the prophylaxis or treatment of autoimmune diseases such as rheumatoid arthritis and the like. In addition to the aforementioned effect, a compound that inhibits production of IL-15 itself or production of inflammatory cytokines, such as TNF-α and the like, which is derived by IL-15, is likely to show a superior effect for the prophylaxis or treatment of autoimmune diseases such as rheumatoid arthritis and the like. However, there is no report taking note of IL-15, which concerns a compound having an inhibitory effect on the proliferation of activated lymphocytes as a therapeutic agent for autoimmune diseases or as a therapeutic agent for RA.
Bioorganic and Medicinal Chemistry Letters, vol. 8, pp. 2787–2792, 1998 discloses a pyrazolecarboxamide compound useful as an immunosuppressant agent. As phenylpyrazolecarboxamide having similar structure, JP-A-52–87168 discloses a compound as an antimicrobial agent, WO97/11690 discloses a compound for treating bacterial infection in which a therapeutically effective amount of an inhibitor of global regulator of pathogenic gene is administered to mammals. Veshchestva, vol. 23, pp. 82–87, 1991 discloses a compound as an agricultural chemical to inhibit growth of plants. However, an inhibitory effect on the proliferation of activated lymphocytes taking note of IL-15 on these compounds is not disclosed at all.
In view of the above, the present inventors have conducted intensive studies and found that an amide compound of the following formula and a pharmaceutically acceptable salt thereof suppress cytokine response that may induce proliferation, differentiation and the like of various cells responsible for immunity, such as lymphocytes (T cells, B cells), macrophages and the like, by the addition of a cytokine, such as IL-2, IL-4, IL-7, IL-9, IL-13, IL-15 and the like, in the presence or absence of an antigen or mitogen. In particular, they have found that the above compound and its salt inhibit IL-15-dependent proliferation of activated lymphocytes and production of inflammatory cytokine derived by IL-15, namely, IL-1, IL-6, IL-12, IL-15, IL-18, TNF-α and the like, which resulted in the completion of the present invention.